Group A streptococci remain an important cause of morbidity and mortality as a result of infections and as a consequence of the postinfectious sequela of acute rheumatic fever. Rheumatic fever and chronic rheumatic heart disease are leading causes of cardiovascular death and disability in developing countries, and have recently increased in incidence in the U.S. Among the potential virulence factors contributing to the pathogenesis of streptococcal diseases, the role of the hyaluronic acid capsule is perhaps the least well understood. The objective of this proposal is to elucidate the role of the capsule both in virulence and in the immune response to streptococcal infection. Both microencapsulated and unencapsulated isogenic mutant strains will be derived from a mucoid (i.e., highly encapsulated) strain of group A Streptococcus by transposon mutagenesis. These mutant strains will be used to examine the role of the capsule in virulence. Specifically, the ability of strains with altered capsule expression to produce lethal infection in mice will be compared with that of the wild type mucoid strain. The effect of partial or complete loss of capsule expression on resistance to phagocytosis will be examined using an in vitro assay of opsonophagocytosis. The mutant strains will also be studied in a mucosal colonization model to determine the effect of degree of encapsulation on the establishment and persistence of mucosal colonization, and on the humoral immune response to both colonization and infection. These studies will lead to a better understanding of the pathogenesis of streptococcal infection and of the immune responses of the host which may play a role in acute rheumatic fever.